Aging is a degenerative biological process that affects multiple organs including kidneys. The kidney function declines in the aged population. The aging-related kidney damage is an important aging process that determines the lifespan. The incidence of kidney damage increases in the aged population. For instance, the prevalence of chronic kidney disease (CKD) is higher in the aged than in the young population. Arterial stiffening, hypertension and angiogenesis are associated with CKD. CKD eventually results in multiple organ dysfunctions leading to heart failure and stroke. However, the etiology and pathogenesis of aging-related kidney damage are poorly understood. Klotho is a recently-discovered anti-aging gene. In humans, the klotho level declines in the aged population. Mutation of klotho gene shortens the lifespan while overexpression of klotho gene extends lifespan in mice. Klotho is predominately expressed in the kidney. CKD is associated with disrupted expression of renal klotho. Our new exciting preliminary data showed kidney-specific knockout of klotho gene caused interstitial fibrosis and glomerulosclerosis and impaired renal function in mice. The preliminary study also demonstrated that renal klotho expression was markedly decreased in the aging kidneys. The overall objective of this application is to determine if klotho plays a role in the maintenance of normal kidney structure and function and if klotho deficiency is involved in the pathogenesis of aging-related kidney damage (interstitial fibrosis, glomerulosclerosis, and impaired kidney function). This objective will be achieved by pursuing two coherent specific aims using a combination of several novel approaches including conditional gene knockout and in vivo tubule cell- specific and podocyte-specific gene delivery. The two specific aims are: (1) Determine if klotho deficiency causes kidney damage and related cellular and molecular mechanisms. (2) Determine if in vivo delivery of klotho gene attenuates the aging-related impairment in kidney structure and function in F344 rats. These studies will demonstrate an important role of klotho in the maintenance of normal kidney structure and function. The results will reveal novel molecular pathways that mediate the pathogenesis of aging-related kidney damage. Completion of this project may offer new insights into therapeutic strategies for aging-related kidney damage.

Public Health Relevance

Kidney disease is associated with aging. For instance, the prevalence of kidney damage is increased in the aged population. The aging-related kidney damage is an important aging process that determines the lifespan. The purpose of the proposed research is to assess if deficiency of klotho, a recently-discovered anti-aging gene, plays a role in the pathogenesis aging-related kidney damage. The results will provide novel information that klotho may protects the kidney. Completion of the project may offer a new therapeutic approach for kidney disorders. The finding will benefit the US population which has a high prevalence of kidney disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK093403-02
Application #
8499299
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Rys-Sikora, Krystyna E
Project Start
2012-06-26
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$305,680
Indirect Cost
$95,792
Name
University of Oklahoma Health Sciences Center
Department
Physiology
Type
Schools of Medicine
DUNS #
878648294
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117
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Jung, Dongju; Xu, Yuechi; Sun, Zhongjie (2017) Induction of anti-aging gene klotho with a small chemical compound that demethylates CpG islands. Oncotarget 8:46745-46755
Chen, Peter Gin-Fu; Sun, Zhongjie (2017) AAV Delivery of Endothelin-1 shRNA Attenuates Cold-Induced Hypertension. Hum Gene Ther 28:190-199
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Zhou, Xiaoli; Chen, Kai; Wang, Yongjun et al. (2016) Antiaging Gene Klotho Regulates Adrenal CYP11B2 Expression and Aldosterone Synthesis. J Am Soc Nephrol 27:1765-76
Chen, Jianglei; Lin, Yi; Sun, Zhongjie (2016) Deficiency in the anti-aging gene Klotho promotes aortic valve fibrosis through AMPK?-mediated activation of RUNX2. Aging Cell 15:853-60
Lin, Yi; Sun, Zhongjie (2015) Antiaging Gene Klotho Attenuates Pancreatic ?-Cell Apoptosis in Type 1 Diabetes. Diabetes 64:4298-311

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